Reduced levels of neurotransmitters including acetylcholine occur in dementias of the Alzheimer type. In particular, a deficit in acetylcholine-mediated transmission is thought to contribute to the cognitive and neurobehavioral abnormalities associated with these disorders. Accordingly, drugs known to augment cholinergic transmission in the CNS are the mainstay of current therapy.
Acetylcholinesterase inhibitors (AChEIs) are now not only part of the standard of care for patients suffering from a dementia of the Alzheimer type, but are also widely used off-label for various other chronic progressive disorders of cognitive function. AChEIs have the enhancement of acetylcholine-mediated neurotransmission as a general mechanism of action. All act in the human CNS to increase and prolong the availability of acetylcholine by inhibiting its degradatory enzyme acetylcholinesterase (AChE). Four AChEIs have been approved by the U.S. FDA for the treatment of dementias of the Alzheimer type: tacrine, donepezil [Aricept®], rivastigmine [Exelon®] and galantamine [Razadyne®]. Rivastigmine has also been approved for the treatment of Parkinson's disease dementia. AChEIs are available in various formulations including immediate release forms such as tablets, capsules and solutions as well as rapid dissolving and extended release forms for oral administration as well as those for parenteral (e.g. transdermal) administration.
Advantageous AChEIs are those currently used or tested for this indication, and include, but are not limited to, 1,2,3,4-tetrahydro-9-acridinamine (tacrine), and pharmaceutically acceptable salts thereof, in particular the hydrochloride; 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline (ipidacrine) and pharmaceutically acceptable salts thereof, in particular the hydrochloride hydrate; (.+−.)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methy-1]-1H-inden-1-one (donepezil) and pharmaceutically acceptable salts thereof, in particular the hydrochloride, 3-[2-(1-benzyl-4-piperidyl)ethyl]-5,7,-dihydro-6H-pyrrolo[3,21]-1,2-benzi-soxazol-6-one (icopezil) and pharmaceutically acceptable salts thereof, in particular the maleate, 3-[1-benzylpiperdin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)prop-an-1-one (zanapezil) and pharmaceutically acceptable salts thereof, in particular the fumarate, (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts thereof, in particular the hydrogen (2R,3R)-tartrate (“rivastigmine tartrate”), 4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3-a,3,2-e,f]benzazepin-6-ol (galantamine) and pharmaceutically acceptable salts thereof, in particular the hydrobromide; (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0.sup.2.7-]trideca-2(7),3,10-trien-5-one (huperzine A) and phenserine and its analogs illustrated in U.S. Pat. No. 8,404,701, the contents of which are incorporated herein in their entirety. Other AChEIs include those described in U.S. Pat. No. 6,683,105, which is incorporated herein in its entirety.
As set forth above, tacrine hydrochloride, donepezil hydrochloride, rivastigmine tartrate and galantamine hydrobromide were approved and are used in the treatment of Alzheimer's type dementia, thus being preferred AChEIs. Huperzine
A, which is not an approved drug but is an AChEI currently used for treating Alzheimer type dementia, is included among the preferred AChEIs of the present invention. It is a purified plant (Huperzia serrata) extract identified as (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.02.7]trideca-2(7),3,10-trien-5-one and also obtained by total synthesis (WO 2009/120774).
Huperzine A is available in unit forms at a maximum dose/unit form of 0.2 mg and generally administered twice a day (0.4 mg/day).
Tacrine hydrochloride was approved in oral IR-unit forms at the maximal recommended dose level of 40 mg, and administered alone at a maximal recommended oral daily dose level of 160 mg.
Donepezil hydrochloride is an AChEI approved worldwide in 5-mg and 10 IR-unit forms at the maximal recommended oral dose level of 10 mg, and is administered alone at a maximal recommended oral daily dose level of 10 mg. It is also approved, in the U.S.A only, in a 23-mg oral unit form that is orally administered alone once per day, even though the benefit/risk ratio of this formulation, when administered alone, has been questioned because it is not tolerated in most patients.
Galantamine, as hydrobromide, was approved in oral IR-unit forms at the maximal recommended oral dose level (in galantamine) of 12 mg, and in oral ER-unit forms at the maximal recommended oral dose level of 24 mg, and is orally administered alone at a maximal recommended daily dose level (in galantamine) of 24 mg.
Rivastigmine, as tartrate, was approved in oral IR-unit forms at the maximal recommended dose level (in rivastigmine) of 12 mg per day, given as two 6 mg doses (one in the morning and one in the evening), or as three 4mg doses (morning, noon, and evening) and, as free base, in ER-unit patch-form, at an initial daily dose of 4.6 mg/24 hours, at a daily tolerated dose of 9.5 mg/24 hour, and at the maximal recommended dose level of 13.3 mg/24 hours rivastigmine release.
In particular, rivastigmine is presented in capsules containing its hydrogen tartrate in amounts corresponding to 1.5, 3, 4.5 and 6 mg of rivastigmine base, as oral solution containing the tartrate corresponding to 2 mg of rivastigmine base and in form of a transdermal patch releasing rivastigmine at 4.6 mg/24 hours or 9.5 mg/24 hours, the recommended daily dosage for the IR forms being of from 6 to 12 mg, divided into 2 doses. The rivastigmine patch, Exelon®, is available as a 5 cm2 patch, containing 9 mg rivastigmine, which delivers 4.6 mg rivastigmine in 24 hours, a 10 cm2 patch containing 18 mg rivastigmine, which releases 9.5 mg/24 hours rivastigmine, and a 15 cm2 patch containing 27 mg rivastigmine, that releases 13.3 mg/24 hours rivastigmine.
AChEIs vary in their pharmacological profiles and in their affinities for acetylcholinesterase and butyrylcholinesterase. Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase enzymes with similar affinity (Thomsen et al., Life Scie. 1990, 46, 1553-58), which is incorporated herein by reference in its entirety.
Carefully conducted clinical trials of rivastigmine (Rösler et al., Brit. Med. J. 1999, 318, 633-38; Farlow et al. Eur. Neurol., 2000, 44, 236-41), which is herein incorporated by reference in its entirety, in patients with dementias of the Alzheimer type demonstrated small, but statistically significant, benefits on cognitive and global measures relevant to dementia. The magnitude of the effect in pivotal clinical trials was of the order of a 2.8 point improvement on the 70-point cognitive subscale of the Alzheimer' s Disease Assessment Scale (ADAS-Cog), or 1-1.5 point improvement on the 30-point Mini-Mental Status Examination (MMSE) compared to placebo over six months.
Moreover, rivastigmine was given open-label to patients with Parkinson's disease (PD) at an initial dose of 1.5 mg twice a day and the dose was increased after 4 weeks to 3 mg twice daily, after 8 weeks to 4.5 mg twice daily and after 12 weeks to a maximal dose of 6 mg twice daily by trying to keep the dose of rivastigmine constant at the maximal 12 mg/day recommended dose, between weeks 12 and 26 of the trial. According to the Authors, rivastigmine may improve the cognitive functions in PD patients with dementia with no worsening of motor function. (Giladi et al., Acta Neurol Scand 2003, 108, 368-373), which is herein incorporated by reference in its entirety.
Unfortunately, however, none of the currently available medications offers more than modest clinical benefit for patients suffering from any of the aforementioned dementing disorders, even when these medications are administered at their maximum recommended dose. This is the first problem limiting the success of current AChEI therapy of Alzheimer type dementias.
A second problem limiting the success of current AChEI therapy of Alzheimer type dementias is that, even at recommended amounts, all these drugs produce dose limiting adverse reactions, mainly if not exclusively, by over-stimulating peripheral cholinergic receptors of the muscarinic type. As a result, signs and symptoms of untoward gastrointestinal, pulmonary, cardiovascular, urinary, and other systems dysfunction occur. These side effects commonly include, for rivastigmine, anorexia, nausea, vomiting, diarrhea, abdominal pain, weight loss; increased bronchial secretions, dyspnea, bronchoconstriction and bronchospasm; bradycardia, supraventricular cardiac conduction abnormalities, vasodilation, hypotension, dizziness and syncope; urinary bladder spasm, increased urinary frequency, and incontinence; flushing and diaphoresis; fatigue, headache, lacrymation, miosis, and loss of binocular vision (Physicians' Desk Reference 2008, Thomson PDR, Montvale, N.J.).
Adverse events attending the use of AChEIs appear to primarily reflect the excessive stimulation of peripheral cholinergic receptors, especially those of the muscarinic type (mAChRs). Five subtypes of muscarinic receptors, M1 through M5, have now been identified. Ongoing research has begun to map the distribution and physiologic role of these receptors as well as determine the binding affinity of drugs to them. For example, M1 receptors are found in sympathetic postganglionic neurons (autonomic ganglia), in gastric tissue and in the myenteric plexus; they are involved in secretions from salivary glands and the gastrointestinal tract. M2 receptors are present in cardiac and smooth muscle and have been implicated in the regulation of contractile forces of the atrial cardiac muscle and the conduction velocity of the atrioventricular node and thus heart rate. M2 receptors are also present on gastrointestinal smooth muscle as well as on detrusor smooth muscle cells and other structures within the bladder wall. M3 receptors are the predominant muscarinic receptor subtype mediating contraction of the stomach fundus, urinary bladder, and trachea. They are also expressed on glandular cells including gastric parietal cells and on vascular smooth muscle as well as detrusor smooth muscle and other structures within the bladder wall. M3 receptors are involved in exocrine gland secretion, smooth muscle contractility, emesis, pupil dilatation, food intake and weight gain.
It is also known that the degree to which AChEIs can attenuate the activity of this enzyme (acetylcholinesterase, AChE) in the CNS can be estimated by assays of AChE activity and related protein levels in the CSF and by use of cerebral imaging technology. It is reported that recommended maximal dose levels of these drugs typically achieve only less than 30% AChE inhibition (without a concomitant increase in AChE protein levels) in the CNS of Alzheimer disease patients (Kuhl et al, Ann Neurol Mar; 49[3]:416-417; Kaasinen V et al, Clin Psychopharmacol. 2002 December, 22[6]:615-20; Sinotoh et al. Curr Pharm Des, 2004; 10[13]:1505-17; Bohnen et al J Neurol Neurosurg Psychiatry, 2005 March; 76[3]:305; OtaT et al, Clin Neuropharmacol, 2010 March-April; 33[2]:74-8 ; Brannan S et al. ACNP 46th Annual Meeting, Program No. 4. Boca Raton Fla., Dec. 10, 2007—“Brannan 2007”; Farlow M et al AAN Poster 2008; Davidsson P et al Neurosci Lett 2001; 300:157-60; Amici S et al Mech Ageing Dev 2001; 122:2057-62), the disclosures of which are each herein incorporated by reference in their entirety, and that inhibition of AChE activity and cognitive improvement are significantly correlated (Giacobini et al. J Neural Transm. 2002 July; 109(7-8):1053-65; Darreh-Shori T et al, J Neural Trans 2006; 113:1791-801), the disclosures of which are each herein incorporated by reference in their entirety, and that, ordinarily, a higher degree of enzyme blockade must be attained for maximum functional effect (Jann et al., Clin Pharmacokinet. 2002; 41(10):719-39—“Jann 2002”), the disclosure of which is herein incorporated by reference in its entirety.
An improvement in the treatment of Alzheimer type dementia is attained by a combined therapy associating a non-selective, peripheral anticholinergic agent, at a dose of from 20% to 200% the current daily doses, with an AChEI, at a dose up to about 4 times the maximal recommended dose of said AChEI, as disclosed in U.S. Pat. No. 8,404,701, the disclosure of which is herein incorporated by reference in its entirety. By such a treatment, a higher acetylcholinesterase inhibition in the CNS is achieved and greater relief of the symptoms of Alzheimer type dementia is enabled, by concomitantly decreasing concurrent adverse effects. Accordingly, for example, rivastigmine may be administered at a daily oral dose of up to 48 mg in combination with an nsPAChA.
In addition, U.S. Pat. No. 8,877,768, the disclosure of which is herein incorporated by reference in its entirety, discloses an improvement in the treatment of Alzheimer type dementia, which is attained by a combined therapy associating a non-anticholinergic-antiemetic agent, at a dose of from 50% to 300% the current IR daily doses, with an
AChEI, at a dose up to 4 times the maximal recommended doses of said AChEI when administered alone.
Similarly, WO 2014/039637, the disclosure of which is herein incorporated by reference in its entirety, discloses the discovery of the property of the non-selective, peripheral anticholinergic agent of increasing the blood levels of a concurrently administered AChEI. Thus, this document recommends the use of high doses of both the non-selective, peripheral anticholinergic agent and of the AChEI in order to ameliorate the symptoms of Alzheimer's dementia. In particular, this document states that “[w]hile potentially lessening side effects and thereby enabling the use of higher and thus more effective doses of the AChEI, merely employing the concomitant use of antiemetics, such as domperidone and others, or of anticholinergics such as propantheline, oxybutynin, tolterodine and others, falls short of achieving the utmost therapeutic advantages of AChEIs in the treatment Alzheimer type dementias”.
Thus, U.S. Pat. No. 8,404,701 and, especially, WO 2014/039637 specifically exclude anticholinergic agents which are selective and/or non-peripheral because selective agents are not able to counteract the whole spectrum of the AChEIs' adverse effect and, worse, the non-peripheral anticholinergics, such as oxybutynin, are able to dangerously counteract the beneficial central action of said AChEIs.
The literature discloses pharmaceutical compositions and Transdermal Therapeutic Systems (TTS) delivering oxybutynin through the human skin.
For example, U.S. Pat. Nos. 5,411,740 and 5,500,222, the disclosures of which are herein incorporated by reference in their entirety, disclose a patch for the transdermal administration of oxybutynin base using a monoglyceride or a mixture of monoglycerides of fatty acids as skin permeation-enhancer.
U.S. Pat. Nos. 5,686,097; 5,747,065; 5,750,137 and 5,900,250, the disclosures of which are herein incorporated by reference in their entirety, disclose a patch for the transdermal administration of oxybutynin base using a monoglyceride or a mixture of monoglycerides plus a lactate ester as skin permeation-enhancer.
A similar patch, adding a non-rate controlling tie layer on the skin-proximal surface of the reservoir, not affecting the drug release, is described in U.S. Pat. Nos. 5,614,211 and 5,635,203, the disclosures of which are herein incorporated by reference in their entirety.
U.S. Pat. Nos. 5,212,199, 5,227,169, 5,601,839 and 5,834,010, the disclosures of which are incorporated herein by reference in their entirety, disclose a patch for transdermal administration of basic drugs using triacetin as permeation enhancer.
U.S. Pat. No. 6,555,129, the disclosure of which is herein incorporated by reference in its entirety, discloses a TTS substantially consisting of an oxybutynin-containing matrix mass in the form of a layer which is self-adhesive, and in which the matrix mass consists of ammonium-group-containing (meth)acrylate copolymers, at least one citric acid triester and 5-25% by weight of oxybutynin.
U.S. Pat. No. 6,562,368, the disclosure of which is herein incorporated by reference in its entirety, discloses a method for transdermally administering oxybutynin using a composition in form of a patch, a cream, a gel, a lotion or a paste comprising oxybutynin and a hydroxide-releasing agent substantially consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.
U.S. Pat. Nos. 6,743,411; 7,081,249; 7,081,250; 7,081,251; 7,081,252 and 7,087,241, the disclosures of which are herein incorporated by reference in their entirety, disclose a transdermal patch delivering a composition comprising oxybutynin to a subject to provide a plasma area under the curve ratio of oxybutynin to an oxybutynin metabolite of from about 0.5:1 to about 5:1, optional in the presence of a permeation enhancer.
U.S. Pat. Nos. 7,029,694; 7,179,483; 8,241,662 and US 2009/0018190, the disclosures of which are herein incorporated by reference in their entirety, disclose a transdermal gel formulation comprising oxybutynin providing a plasma area under the curve ratio of oxybutynin to an oxybutynin metabolite of from about 0.5:1 to about 5:1, optional in the presence of a permeation enhancer.
US 2004/0219194, the disclosure of which is herein incorporated by reference in its entirety, discloses a transdermal therapeutic system containing oxybutynin, triacetin and Aloe vera extract as permeation enhancer.
US 2004/0057985, the disclosure of which is herein incorporated by reference in its entirety, discloses transdermal therapeutic systems (TTS) for the administration of oxybutynin with which therapeutically active absorption rates can be achieved without the necessity of adding permeation-enhancing substances. These TTS comprise a substantially water vapor-impermeable backing layer, at least one pressure-sensitive adhesive matrix layer attached thereto, and a detachable protective film, said matrix layer comprising an inner phase containing the active substance oxybutynin, and an outer, pressure sensitive adhesive phase based on hydrocarbon polymers or/and silicone polymers.
US 2005/0064037, the disclosure of which is herein incorporated by reference in its entirety, discloses an oxybutynin gel formulation topical gel formulation comprising oxybutynin chloride salt, a short chain alcohol, a gelling agent substantially consisting of high-molecular-weight, cross-linked polymer of acrylic acid or cross-linked copolymer of acrylic acid and C10-30 alkyl acrylate, and optionally a permeation enhancer substantially consisting of propylene glycol, propylene glycol laurate, isopropyl myristate, and methyl lactate.
WO 2005/039531, US2007/022379, US 2010/0216880, US 2014/0037713 and U.S. Pat. No. 8,652,491, the disclosures of which are herein incorporated by reference in their entirety, disclose a transdermal or transmucosal pharmaceutical formulation, that can be utilized for topical or transdermal application, such that solutions, creams, lotions, sprays, ointment, gels, aerosols and patch devices, for the delivery of one or more active agents, including anticholinergics, in particular oxybutynin. Said formulation includes oxybutynin in a solvent system comprising a diethylene glycol monoalkyl ether and a glycol in specific ratios, alcohol and water. In particular, according to U.S. Pat. No. 8,652,491 a possible secondary active agent, in addition to the anti-cholinergic agent such as oxybutynin, may be an antiperspirant, a tranquilizer or another agent capable of ameliorating hyperhidrosis.
WO 2005/107812, U.S. Pat. No. 7,425,340 and US 2008/0260842, the disclosures of which are herein incorporated by reference in their entirety, disclose formulations containing an anticholinergic agent, in particular oxybutynin, in admixture with urea, urea congeners or urea-containing compounds as permeation enhancers.
WO 01/07018 and U.S. Pat. No. 8,420,117, the disclosures of which are herein incorporated by reference in their entirety, disclose a matrix patch formulation containing no water for external use, comprising, as essential components oxybutynin hydrochloride, citric acid and sodium acetate.
WO2013/061969 and US 2014/0271796, the disclosures of which are herein incorporated by reference in their entirety, disclose a transdermal absorption preparation comprising at least one drug selected from oxybutynin and pharmaceutically acceptable salts thereof; and a sterol such as cholesterol, cholesterol derivatives and cholesterol analogs.
U.S. Pat. No. 8,802,134, the disclosure of which is herein incorporated by reference in its entirety, discloses a method for producing a patch wherein oxybutynin is incorporated in an adhesive agent layer composition comprises the acrylic-based polymer as the adhesive base agent, and the acrylic-based polymer is a copolymer of polymethyl methacrylate with a polyacrylate.
U.S. Pat. No. 8,877,235, the disclosure of which is herein incorporated by reference in its entirety, discloses a patch consisting of a support layer and of an adhesive agent layer arranged on the at least one surface of the support layer, the adhesive agent layer comprising oxybutynin hydrochloride in a supersaturated concentration in a dissolved form. Said layer also comprises acrylic-based polymers and rubber-based polymers, as adhesive base agents, and liquid paraffin, a sterol, an organic acid, and a tackifier.
The disclosures of the aforementioned documents are incorporated herein by reference in their entirety.
Oxybutynin is a well-known non-selective anticholinergic medication used to relieve urinary and bladder difficulties, including frequent urination and urge incontinence and all the above references emphasize this use. However, as set forth above, oxybutynin is not “peripheral” as per the definition given above because it is able to cross the blood brain barrier (“BBB”) to a non-negligible extent (Rebecca J McCrery and Rodney A Appell, Ther Clin Risk Manag. March 2006; 2/1: 19-24).
Oxybutynin is commercially presented in a 39-cm2 patch system containing 36 mg of oxybutynin and releasing 3.9 mg/day oxybutynin (OXYTROL®). This patch provides significant improvements in all the measured parameters with less systemic adverse effects, as summarized by J. Jayarajan and S. B. Radomski in a review presented on 4 Dec. 2013: “Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability, and quality of life” (J. Jayarajan et al., Research and Reports in Urology 2014:6), the disclosure of which is herein incorporated by reference in its entirety. However, oxybutynin is anyway deemed to cross the BBB owing to its high lipophilicity, neutrality, and small molecular size (C. A. Donnellan et al. BMJ 1997; 315:1363-4; R. Scheife and M. Takeda, Clin Ther. 2005; 27:144-53). the disclosure of which is herein incorporated by reference in its entirety.
Oxybutynin is also commercially presented (GELNIQUE®) in a TTS consisting of a hydroalcoholic gel containing 100 mg oxybutynin chloride per gram of gel and available in a 1 gram (1.14 ml) unit dose. This TTS is deemed to have a pharmacokinetic profile similar to that of the patch delivery system, while producing lower N-desethyloxybutynin metabolite plasma concentrations (Vincent R Lucente et al.; Open Access Journal of Urology 2011/3, 35-42). Another commercial TTS system, presents oxybutynin in a hydroalcoholic gel containing 30 mg oxybutynin base per gram of gel and is available (ANTUROL®) in a 0.92 gram (1 mL) unit dose that contains 28 mg oxybutynin per gram of gel. Also Anturol® demonstrated plasma levels of oxybutynin comparable to the efficacious plasma levels observed for oral and patch therapies with lower N-desethyloxybutynin plasma levels (Anturol® Gel Summary by Antares Pharma).
Oxybutynin is a very good tool for administering anticholinergic therapy. Administered orally to mice, it has been shown to cross the Blood-Brain-Barrier. Even when given by transdermal route, oxybutynin has been shown to penetrate the brain. Studies with radiolabeled [14C] oxybutynin administered transdermally to rats have shown presence of radiolabel in the brain [Pharmaceutical and Medical Devices Agency Interview Form (PMDA is the Japanese Regultaory Agency, equivalent to FDA in the US]. The label for transdermal oxybutynin warns that a variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment. The label further advises that patients should be told not to drive or operate heavy machinery until they know how transdermal oxybutynin affects them. The label also advises that if a patient experiences anticholinergic CNS effects, drug discontinuation should be considered. In addition, the label states that overdosage with oxybutynin has been associated with CNS anticholinergic effects including excitation, memory loss, stupor, disorientation and agitation on awakening. Hence, based on the existing literature, and the competing action of oxybutynin and an AChEI in the CNS, the combined use of such drugs would have made memory loss a-priori material risk for the treatment of Alzheimer type dementia.